Isostructural folate conjugates radiolabeled with the matched pair 99mTc/188Re: a potential strategy for diagnosis and therapy of folate receptor-positive tumors.

Abstract

UNLABELLED:

(99m)Tc-technetium ((99m)Tc) and (188)Re-rhenium ((188)Re) represent an interesting pair of radionuclides for diagnosis and therapy. The aim of this study was to synthesize and characterize in vitro/in vivo the first (188)Re-folate derivative [(188)Re(CO)(3)-picolylamine monoacetic acid 188/Re-OANA-folate (2)] for potential targeted radionuclide therapy of FR-positive tumors. The data were compared with those of the isostructural (99m)Tc-analog [(99m)Tc-PAMA folate (1)] reported previously.

METHODS:

In vitro stability of compound 2 was tested in phosphate-buffered saline and human plasma. Cell binding experiments were performed with FR-positive human KB cells. Biodistribution was assessed in female nude mice, bearing KB tumor xenografts.

RESULTS:

Cell binding experiments showed high and FR-specific uptake. In vivo, compound 2 accumulated specifically in the FR-positive tumors with maximal values 4 h post injection (p.i.) ['2: 1.87+/-0.04 percent injected dose per gram of weight tissue (% ID/g) vs. '1: 2.33+/-0.36% ID/g]. Unfavorably high retention of radioactivity was found in FR-positive kidneys (12.04+/-0.62% ID/g; 4 h p.i.). Tumor-to-blood ratio of radioactivity ('2: 14.5+/-1.32, 4 h p.i.) was lower than for compound '1 (58.0+/-12.2, 4 h p.i.), whereas tumor-to-kidney ratios were in the same range ('2: 0.15+/-0.01 vs. '1: 0.13+/-0.02, 4 h p.i.). Preadministration of the antifolate pemetrexed significantly improved the tumor-to-kidney ratio (2: 1.59+/-0.30, 4 h p.i.).

CONCLUSIONS:

The isostructural radiofolates 1 and '2 displayed almost identical pharmacokinetic profiles and accumulated both specifically in FR-positive tumors. However, only the coapplication of the antifolate pemetrexed improved the biodistribution of the radiotracers in such ways that a potential therapeutic application of compound '2 can be envisaged in the future.

• Authors: Cristina Müller, P August Schubiger, Roger Schibli
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 34 Issue 6 Pg. 595-601 (Aug 2007) ISSN: 0969-8051 [Print] United States
• PMID: 17707798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Buffers
• Carrier Proteins
• Folate Receptors, GPI-Anchored
• Folic Acid Antagonists
• Glutamates
• Phosphates
• Radioisotopes
• Radiopharmaceuticals
• Receptors, Cell Surface
• Pemetrexed
• Guanine
• Rhenium
• Technetium
• Folic Acid

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Buffers
• Carrier Proteins (metabolism)
• Female
• Folate Receptors, GPI-Anchored
• Folic Acid (chemistry)
• Folic Acid Antagonists (pharmacokinetics, therapeutic use)
• Glutamates (pharmacokinetics, therapeutic use)
• Guanine (analogs & derivatives, pharmacokinetics, therapeutic use)
• Humans
• Isotope Labeling
• KB Cells
• Kidney (metabolism)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neoplasms (drug therapy, metabolism)
• Pemetrexed
• Phosphates (chemistry)
• Radioisotopes
• Radiopharmaceuticals (chemical synthesis, chemistry, pharmacokinetics)
• Receptors, Cell Surface (metabolism)
• Rhenium (chemistry)
• Technetium (chemistry)
• Tissue Distribution